JOURNAL OF MEDICAL CASE REPORTS Severe community-acquired adenovirus pneumonia in an immunocompetent 44-year-old woman: a case report and review of the literature Clark et al. Clark et al. Journal of Medical Case Reports 2011, 5:259 http://www.jmedicalcasereports.com/content/5/1/259 (30 June 2011) CASE REP O R T Open Access Severe community-acquired adenovirus pneumonia in an immunocompetent 44-year-old woman: a case report and review of the literature Tristan W Clark * , Daniel H Fleet and Martin J Wiselka Abstract Introduction: This case report describes a rare condition: community-acquired adenovirus pneumonia in an immunocompetent adult. The diagnosis was achieved by using a multiplex real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay and highlights the usefulness of these novel molecular diagnostic techniques in patients hospitalized with acute respiratory illness. We also performed a literature search for previously published cases and present a summary of the clinical, laboratory and radiological features of this condition. Case presentation: A 44-year-old immunocompetent Caucasian woman was admitted to our hospital with an acute febrile respiratory illness associated with a rash. Her blood tests were non-specifically abnormal, and tests for bacterial pathogens were negative. Her condition rapidly deteriorated while she was in our hospital and required mechanical ventilation and inotropic support. A multiplex real-time RT-PCR assay performed on respiratory specimens to detect respiratory viruses was negative for influenza but positive for adenovirus DNA. The patient recovered on supportive treatment, and antibiotics were stopped after 5 days. Conclusions: Community-acquired adenovirus pneumonia in immunocompetent adult civilians presents as a non- specific acute febrile respiratory illness followed by the abrupt onset of respiratory failure, often requiring mechanical ventilation. Its laboratory and radiological features are typical of viral infections but also are non- specific. Novel multiplex real-time RT-PCR testing for respiratory viruses enabled us to rapidly make the diagnosis in this case. The new technology could be used more widely in patients with acute respiratory illness and has potential utility for rationalization of the use of antibiotics and improving infection control measures. Introduction Adenoviruses are double-stranded DNA viruses belong- ing to the family Adenovi ridae. There are over 50 known serotypes of adenovirus, which a re categorized into six subgenera (A to F). Adenoviruses are a common cause of acute febrile and respiratory infections in children and are generally self -limiting [1]. Severe infections, including pne umonia, can occur in neonates [2] and in adults with compromised immunity, such as those with hematopoie- tic stem cell transplants and in patients with human immunodeficienc y virus (H IV) infection [3]. Outb reaks of acute respiratory illness, including pneumonia, caused byadenovirusserotypes3,4,7,14and21arecommon among military recruits, and fatal outcomes have occa- sionally been reported [4-6]. Outbr eaks of adenovirus infection i n long-term nursing facilities and in hospital wards with associ ated cases of fatal pneumonia have also been described [7]. In contrast, community-acquired ade- novirus pneumonia in immunocompetent adult civilians has rarely been described. We report the case of a pre- viously healthy and immunocompetent woman with severe adenovirus pn eumonia who developed rapidly progressive respiratory fail ure requiring mechanical ven- tilation an d who made a successful recovery after being treated with supportive measures. We also s ummarize the demographic, clinical, laboratory and radiological fea- tures of community-acquired adenovirus pneumonia cases in immunocompetent adult civilians that have pre- viously been reported in the literature. * Correspondence: twc74@hotmail.co.uk Department of Infectious Diseases, Leicester Royal Infirmary, Level 6 Windsor Building, Leicester, LE1 5WW, UK Clark et al. Journal of Medical Case Reports 2011, 5:259 http://www.jmedicalcasereports.com/content/5/1/259 JOURNAL OF MEDICAL CASE REPORTS © 2011 Clark et al; licensee BioMed Central Ltd. This is an Open Access ar ticle distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licens es/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Case presentation A 44-year-old Caucasian woman was admitted to our emergency department with a three-day history of a feb- rile illness associated with sore throat, dry cough, myal- gia and diarrhea. One day prior to admission she had developed a widespread, non-pruritic, erythematous rash. Her medical history consisted of hypertension, for which she was taking atenolol, and several episodes of gout, for which she was taking allopurinol. Her physical examination revealed that she was obese, had a body temperature of 39.0°C, a pulse rate of 112beats/ minute and blood pressure of 145/90 mmHg. Her respira- tory rate was 20 breaths/minute with oxygen saturation of 94% on room air. Her chest auscultation was unremark- able. She had a widespread, erythematous maculopapular rash with scattered petechiae on both legs. Examination of the oropharynx revealed erythema but no exudate. Initial laboratory tests showed a white cell count of 9.2 ×10 9 /L, a neutrophil count of 7.9 × 10 9 /L, a lymphocyte count of 0.69 × 10 9 /L, a platelet count of 254 × 10 9 /L, a C-reactive protein concentration of 169 mg/L, an a la- nine aminotransferase level of 22 IU/mL, a creatinine phosphokinase (CPK) levelof950IU/mLandacreati- nine concentration of 73 μmol/L. Her HIV test was negative. Her anti-nuclear antibodies, rheumatoid factor and anti-neutrophil cytoplasmic antibodies were nega- tive, and her complement components C3 and C4 and immunoglobulin levels were within the normal range. Her initial ches t radiograph was unremarkable. She was commenced on intravenous ceftriaxone for presumed meningococcal disease. Twenty-four hours following admission her condition rapidly deteriorated with acute respiratory failure and hypotension requiring admission to the intensive care unit for mechanical ventilation and vasopressor support. A repeat chest radiograph showed widespread interstitial infiltrates bilaterally (Figure 1). Her antibiotics were changed to imipenem and doxycycline to treat pre- sumed bacterial pneumonia, and oseltamivir was empiri- cally added to treat a possible 2009 pandemic influenza A (H1N1) infection. Bacterial cultures of her blood and sputum, Legionella antigen testing of her urine, and a polymerase chain reaction (PCR) assay of her blood for Neisseria meningi- tidis and Streptococcus pneumoniae were all negative. Her nasopharyngeal and tracheal samples were negative for influenza A and B (including H1N1), respiratory syn- cytial virus (RSV) types A and B and parainfluenza virus (PIV) types 1 thr ough 4, but they were positive for ade- novirusDNAonthebasisofPCRassay(usingthe hexon gene as the target for a mplification), with a cycle threshold value of 18. Subsequent sequencing analysis performed at the respiratory Virus Reference Laboratory, London, revealed the isolate to belong to serotype 4. The patient made an uncomplicated reco very without any specifi c antiviral therapy and was extubated on the fifth day of her admission. Antibiotics were stopped after a total of five days, and she was discharged to home on the ninth day of her admission. Further tests for immunodeficiency were negative. We performed a literature search of MEDLINE for cases of community-acquired adenovirus pneumonia in immunocompetent adults. We used the search terms “adenovirus,”“pneumonia,”“immunocompetent,”“adult” and “civilian.” We excluded cases that involved military recruits, nosocomial cases and those cases in which bac- terial pathogens were also implicated. We identified 19 articles published between 1975 and 2008 [8-26] describing 21 patients that matched our search terms. The demographic, laboratory, radiologica l and clinical details of these cases and our own are shown in Table 1. Of the 21 cases retrieved in our literature search, 57% of the patients were men, and overall the patients’ med- ian age was 40 years (age range, 18 to 60 years). Where recorded, the commonest ethnic origin of patients was Caucasian (40%). Significant co-morbidity was uncom- mon among patients, but obesity was frequently noted as an examination finding. The median duration o f illness prior to admission to the hospital was five days. The following presenting symptoms were no ted: fever (90%) , cough (81%), dys- pnea (70%), myalgia (57%), sore throat (29%), abdominal pain (14%) and diarrhea (10%). Common examination findings on presentat ion included abnormalities in chest auscultation (90%), pyrexia (89%) and hypoxia (66%). The presence of pharyngitis, conjunctivitis or rash was noted infrequently (19%, 19% and 5% respectively). Figure 1 The patient’ s repeat chest radiograph showing widespread bilateral interstitial infiltrates. Clark et al. Journal of Medical Case Reports 2011, 5:259 http://www.jmedicalcasereports.com/content/5/1/259 Page 2 of 5 The median white cell count on admission to the hos- pital was 7.7 × 10 9 (range, 3.9 × 10 9 to 28 × 10 9 ), although neutrophilia was relatively common (33%). Lymphopenia and thrombocytopenia were noted in 52% and 19% of patients, respectively. Other frequently noted laboratory abnormalities were mildly elevated transaminases and elevated levels of CPK. The chest ra diograph at presen tation was abnormal in 90% of patients. The most common pattern of abnorm- ality was bilateral interstitial infiltrates (57%), although lobar consolidation was also noted reasonably frequently (24%). Intubation and mecha nical ventilation were required in 67% of patients and occur red at a median of one and half days following admission. Overall 24% of patients died. The median length of stay in the hospital was 21 days. T wo patients received antiviral therapy with cido- fovir, one of whom died. Where recorded, the most common adeno virus sero- types identified were serotype 7 (24%), serotype 3 (19%), serotype 21 (14%) and serotype 4 (10%). The diagnosis was made most frequently on the basis of lower respira- tory tract samples (principally bronchoscopic alveolar lavage fluid and lung biopsy tissue), and viral culture was the most common method of adenovirus detection (76%). There were no cases identified in the literature where molecular methods were used to diagnose adeno- virus pneumonia. Discussion Our case report and review of the literature provides the first comprehensi ve review of comm unity-acquired ade- novirus pneumonia in immunocompetent adult civilians. Hakim and Tleyjeh [8] published a case report and lit- erature review of adenovirus pneumonia in immuno- competent adults in 2008; howev er, their cohort was a mix of civilians, military recruits and healthcare-asso- ciated cases. The 21 cases we identified in the literature demon- strate that patients with adenovirus pneumonia usually present with several days’ history o f a non-specific feb- rile respiratory illness. These patients frequentl y have respiratory compromise with hypoxia at the time of pre- sentation, while the classical features of adenoviral infec- tion, such as pharyngitis, conjunctivitis, rash or diarrhea, are usually absent. The clinical condition of most patients deteriorates rapidly during a dmission and requires intubation and ventilation, a pattern commonly seen with primary influenza pneumonia [27]. Laboratory findings are also typical of viral infecti on, with a normal Table 1 The demographic, clinical, laboratory, radiological and outcome data for the 21 cases reported in the literature and in our patient a Patient characteristics Our case Previously reported cases (n = 21) Demographics Age, yr 44 40 [18 to 60] Sex Female Male 12 (57) Presenting symptoms Preceding history, days 3 5 [1 to 28] Fever Yes 19 (90) Cough Yes 17 (81) Dyspnea Yes 15 (70) Myalgia Yes 11 (57) Sore throat Yes 6 (29) Abdominal pain Yes 3 (14) Diarrhea Yes 2 (10) Examination findings Fever (temperature > 38°C) Yes 17 (81) Chest signs No 19 (90) Hypoxia No 16 (66) Pharyngitis Yes 4 (19) Conjunctivitis No 4 (19) Rash Yes 1 (5) Laboratory tests Total white cell count (4 to 11 ×10 9 /L) 6.6 7.7 [3.9 to 28] Neutrophilia (> 7 × 10 9 /L) No 7 (33) Lymphopenia (< 1.0 × 10 9 /L) Yes 11 (52) Thrombocytopenia (< 150 × 10 9 /L) No 4 (19) Elevated transaminases No 6 (29) Elevated CPK Yes 6 (29) CXR appearance Normal No 2 (10) Lobar consolidation No 5 (24) Bilateral interstitial infiltrates Yes 12 (57) Clinical course/outcome Required ET intubation Yes 14 (67) Time to Intubation, days 3 1.5 [0.25 to 8] Treatment with cidofovir No 2 (10) Length of hospital stay, days 9 21 [3 to 123] Died No 5 (24) Adenovirus serotype 3 No 4 (19) 4 Yes 2 (10) 7 No 5 (24) 21 No 3 (14) Unknown No 7 (33) a CPK, creatinine phosphokinase; CXR, Chest X ray; ET, endotracheal tube. Data are expressed as n (%) or median [range]. Clark et al. Journal of Medical Case Reports 2011, 5:259 http://www.jmedicalcasereports.com/content/5/1/259 Page 3 of 5 total white cell count, relative lymphopenia, thrombocy- topenia and elevated transaminases and CPK being fre- quently observed. The most commonly seen radiol ogical pattern on admission is widespread bilateral interstitial shadow ing, which is consistent with the results reported in a case series describing the radiological appearance of adult patients with confirmed adenoviral pneumonia [28]. It is noteworthy that several patients, including our own case, had normal initial chest radiography results. Lobar consolidation, a pattern considered more sugges- tive of bacterial infection, was observed in around one- fourth of patients with adenoviral pneumon ia. All of these radiological patterns (including normal initial chest radiographs) have been described in patients with primary influenza pneumonia [29-31]. Although the overall mortality rate in this series [8-26] was 24%, only two patients who were reported on after 1979 have died, possibly representing improvement in supportive care over this time period. Our present case report of an immunocompetent adult civilian patient with sporadic adenoviral pneumo- nia is the first case to be reported in the literature in which molecular diagnostic methods were used. Nucleic acid detection has the advantages of increased sensitivity and rapid availability of results compared to the conven- tional diagnostic techniques of viral culture and antigen detection [32]. In addition, multiplex real-time reverse transcriptase PCR (RT-PCR) assays are increasingly being used by diagnostic laboratories to detect a wide range of respiratory viruses in a single reaction. While it is well-recognized that influenza virus and adenovirus can cause pneumonia, there is increasing evidence that other respiratory viruses, such as RSV, human metap- neumovirus, PIV, human rhinovirus and human corona- virus play an important role in the etiology of community-acquired pneumonia in adults [33]. The increasingly widespread use of multiplex real-time RT- PCR for the detection of respirato ry viruses in clinical practice will allow u s to accurately determine the bur- den of respiratory viral infection in patient s with com- munity-acquired pneumonia and may demonstrate that adenoviral pneumonia in immunocompetent adults is more common than previously thought. The advantages of rapidly diagnosing respiratory viral infection in patients with community-acquired pneumo- nia include the institution of appropriate infection con- trol measures, the rational use of antibiotics in the absence of bacterial co-pathogens and, in some instances, the use of specific antiviral therapy. Two patients in our series [8-26] rec eived the antiviral agent cidofovir, and while there are no randomized, controlled trials demonstrating its efficacy in adenoviral infection, it has been used successfully in immunocompromised patients with severe adenoviral pneumonia [34]. Conclusions Our literature review suggests that community-acquired adenoviral pneumonia in immunocompetent adult civi- lians presents as a non-specific febrile respiratory illness that progresses rapidly to respiratory failure and often requires mechanical ventilation. The laboratory and radiological findings are typical of viral infection but are also non-specific. Novel respiratory virus real-time RT- PCR testing enabled us to rapidly detect adenovirus as the cause of severe community-acquired pneumonia in our patient. Consent Written informed consent was obtained from the patient for publicatio n of this case report and any accompany- ing images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Abbreviations ALT: alanine aminotransferase; ANCA: anti-neutrophil cytoplasmic antibodies; BAL: bronchoscopic alveolar lavage; CPK: creatinine phosphokinase; C t : cycle threshold; RSV: respiratory syncytial virus; RT-PCR: reverse transcriptase polymerase chain reaction. Acknowledgements We acknowledge and thank all the clinical staff involved in the care of our patients and the University Hospitals of Leicester NHS trust microbiology laboratory staff who were involved in the processing and interpretation of patient samples. 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Eur J Clin Microbiol Infect Dis 2004, 23:583-588. doi:10.1186/1752-1947-5-259 Cite this article as: Clark et al.: Severe community-acquired adenovirus pneumonia in an immunocompetent 44-year-old woman: a case report and review of the literatur e. Journal of Medical Case Reports 2011 5:259. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Clark et al. Journal of Medical Case Reports 2011, 5:259 http://www.jmedicalcasereports.com/content/5/1/259 Page 5 of 5 . JOURNAL OF MEDICAL CASE REPORTS Severe community-acquired adenovirus pneumonia in an immunocompetent 44-year-old woman: a case report and review of the literature Clark et al. Clark et al. Journal. performed the literature search and assisted in the writing of the manuscript. MJW oversaw the study and assisted with the writing of the manuscript. All authors read and approved the final version of the. present a summary of the clinical, laboratory and radiological features of this condition. Case presentation: A 44-year-old immunocompetent Caucasian woman was admitted to our hospital with an acute